Changes In Cytokines Research Articles

Lactobacillus helveticus LZ-R-5 Ameliorates DSS-Induced Colitis in Mice by Modulating Gut Microbiota and Enhancing Intestinal Barrier Function.

Lactobacillus helveticus LZ-R-5 (R-5), a strain with high epithelial adhesion and bioactive exopolysaccharide production, was isolated from Tibetan kefir grains. This study investigated its potential to alleviate intestinal inflammation using a DSS-induced colitis model in BALB/c mice. We integrated microbial diversity and serological analyses to assess changes in gut flora and cytokines following the R-5 treatment. Pathological assessments showed that R-5 reduced crypt distortion in the proximal colon and mitigated hepatic immune challenges by enhancing gut barrier function. The increased relative expression of TGF-β1 and the downregulation of NLRP3-related inflammatory factors were conducive to preventing organ damage in the thymus and spleen of mice with colitis. Additionally, R-5 stimulated GPR43 expression and improved epithelial nutrition, promoting mucin production to prevent enterotoxin leakage. It also modulated the gut microbiota by suppressing Bacteroides and Erysipelatoclostridium, leading to a microbiota composition more akin to that of normal flora.

Intraperitoneal immunotherapy with denileukin diftitox (ONTAK) in recurrent refractory ovarian cancer

BackgroundDenileukin diftitox (ONTAK) is a diphtheria/IL-2R fusion protein able to deplete regulatory T cells in peripheral blood. Regulatory T cells in the local immune microenvironment have been shown to be associated with poor prognosis in ovarian cancer. This study examined whether denileukin diftitox (ONTAK) could be safely administered intraperitoneal in patients with advanced refractory ovarian cancer and assessed its effects on regulatory T cells and tumor associated cytokines in ascites and peripheral blood. Patients and methodsA phase I dose escalation study of intraperitoneal denileukin diftitox (ONTAK) enrolled 10 patients with advanced, refractory ovarian carcinoma at 3 doses (5 μg/kg, 15 μg/kg, and 25 μg/kg). Serial CA-125 measurements assessed clinical response. Regulatory T cells were quantified using RT-PCR and cytokine levels measured by Luminex. ResultsThe maximum tolerated dose was 15 μg/kg with a dose limiting toxicity observed in 1 out of 6 patients in the expansion group. The majority of adverse events were transient grades 1–2. One patient treated at the 25 μg/kg dose experienced cytokine storm with prolonged hospitalization. 3 patients had decreases in CA-125 after treatment but none met criteria for partial response. Treatment with denileukin diftitox (ONTAK) decreased regulatory T cells in peripheral blood and ascites. Treated patients did not show any significant changes in IL-8, TGF-β, sIL2Ra in ascites or peripheral blood. ConclusionsDenileukin diftitox (ONTAK) can be safely administered intraperitoneally to recurrent refractory ovarian cancer patients. Regulatory T cells were reduced in ascites and peripheral blood, but there were no significant changes in cytokine levels.Clinical Trial Registration:ClinicalTrials.gov # NCT00357448

Predictors of Gastrostomy Tube Placement in Head and Neck Cancer Patients Undergoing Radiation or Chemoradiotherapy: A Systematic Review.

Malnutrition is a major problem in head and neck cancer (HNC) with up to half of patients requiring gastrostomy tube (G-tube) placement. Predicting this need remains complex given mixed evidence surrounding its usage. A comprehensive search was performed to identify studies examining risk factors associated with G-tube placement following radiotherapy (RT) or concurrent chemoradiotherapy (CCRT)in HNC patients. Sixteen retrospective studies were included (n = 11 015). The overall prevalence of G-tube placement was 44% with 76% of patients receiving reactive G-tube placement. Pretreatment dysphagia, pretreatment BMI < 18.5, and tumors in the hypopharynx were significant predictive factors for prophylactic G-tube placement. Type of chemotherapy regimen, tumors in the nasopharynx, and cytokine changes were significant predictive factors for reactive G-tube placement. Several factors were identified that contribute to increased risk of G-tube placement and may guide current decision-making algorithms.

ASSOCIATION BETWEEN IL-1, IL-6, TGF-β AND IFN-γ SINGLE NUCLEOTIDE POLYMORPHISMS AND AUTISM SPECTRUM DISORDER: SYSTEMATIC REVIEW AND METANALYSIS

Autism spectrum disorders (ASDs) constitute a group of neurodevelopmental disorders with increasing incidence. Cytokine changes may affect the integrity of the central nervous system, contributing to neuroinflammation and behavioral symptoms in patients with ASD. Single nucleotide polymorphisms (SNPs) can lead to immune disorders such as this. Therefore, the aim of the present study was to perform a systematic review and meta-analysis to determine whether cytokine SNPs are more common in individuals with ASD. A systematic search of seven databases was conducted on September 19, 2023. Odds ratios (ORs) were used in the meta-analysis to test the association between each SNP and ASD. Six studies were included. Four cytokines were investigated: interleukin-1 (IL-1), IL-6, transforming growth factor beta (TGF-β) and interferon-γ (IFN-γ). Although some studies alone have associated genotypic and allelic variants with ASD, the pooled results of the studies were not statistically significant in the meta-analysis. Our systematic review highlights important gaps and inspires new studies to investigate significant associations between genetic variations in different cytokines and the development of ASD.

The immune checkpoint molecule B7-H4 regulates β-cell mass and insulin secretion by modulating cholesterol metabolism through Stat5 signalling

BackgroundB7-H4 (B7S1, B7x, VTCN1) is an important immune checkpoint molecule that maintains immune homeostasis and is also expressed in pancreatic β cells. The polymorphism of B7-H4 influences the prevalence of Type 2 diabetes (T2D), suggesting a potential role of B7-H4 in the physiological function of pancreatic β cells and the pathogenesis of T2D. Methodsβ-cell-specific B7-H4 knockout mice (B7-H4 cKO mice) and their wild-type littermates were used to investigate the in vivo effects of B7-H4 on pancreatic β-cell morphology and function. AAV2/8-ins2-B7H4 and a control virus were infused via the pancreatic intraduct into high-fat diet (HFD)-treated mice to elucidate the therapeutic effect of B7-H4. RNA sequencing was conducted on primary islets. A Luminex assay was used to quantify cytokine changes in B7-H4 cKO mice. Electron microscopy imaging was used to observe insulin secretory vesicles in pancreatic β cells. ResultsLesion of B7-H4 in β cells results in glucose intolerance due to reduced β-cell mass and deficient insulin secretion, whereas overexpression of B7-H4 in β cells ameliorates glucose intolerance in HFD-fed mice. Mechanistically, B7-H4 deficiency activates signal transducer and activator of transcription 5 (Stat5) signalling, which inhibits the expression of apolipoprotein F (Apof), leading to reduced cholesterol efflux and accumulated cholesterol in β cells, thereby impairing insulin processing and secretion. Overexpression of Apof in β cells or intraperitoneal injection of a Stat5 inhibitor reverses the metabolic phenotype and insulin secretion deficiency in B7-H4 cKO mice. ConclusionsOur study demonstrated that B7-H4 plays an important role in regulating β-cell mass and insulin secretion, which may shed new light on the development of novel strategies for T2D treatment.

A Cross Sectional Study of Cytokines in Women with Refractory Detrusor Overactivity versus Controls.

Previous work has suggested that refractory detrusor overactivity (DO) was commonly associated with urinary tract infection (UTI), which can lead to inflammatory changes in the bladder. This study aimed to investigate the concentrations of urinary cytokines in a large sample of women with refractory detrusor overactivity (DO) and age matched controls. The urinary concentration of 27 cytokines in 140 women (95 with refractory DO and 45 age matched controls (women without urge incontinence)) was determined using the Human Cytokine 27-plex Assay. Cytokine concentrations were correlated with a "UTI score", the presence or absence of bacteriuria or pyuria on the day of sample collection and a previous history of UTI. Pro-inflammatory cytokines were increased in refractory DO women compared to the controls. In women with refractory DO, the UTI score significantly correlated with urinary cytokine concentrations in 15 of the 22 cytokines detected. A previous history of UTI did not affect urinary cytokine concentrations in refractory DO women with no current UTI. Increasing pyuria was associated with increasing concentrations of urinary cytokines. Careful comparison of cytokine concentrations in women with refractory DO versus age matched controls has shown that changes in pro-inflammatory cytokines are related to the UTI disease burden, suggesting that an underlying inflammatory response, together with UTI, may be an aetiological contributor to the development of refractory DO.

Macrophage-Specific Lactate Dehydrogenase Expression Modulates Inflammatory Function In Vitro.

In acute kidney injury, macrophages play a major role in regulating inflammation. Classically activated macrophages (M1) undergo drastic metabolic reprogramming during their differentiation and upregulate the aerobic glycolysis pathway to fulfill their pro-inflammatory functions. NAD+ regeneration is crucial for the maintenance of glycolysis and the most direct pathway by which this occurs is via the fermentation of pyruvate to lactate, catalyzed by lactate dehydrogenase A (LDHA). Our previous study determined that LDHA is predominantly expressed in the proximal segments of the nephron in the mouse kidney and increases with hypoxia. This study investigates the potential of LDHA as a therapeutic target for inflammation by exploring its role in macrophage function in vitro. Bone-marrow-derived macrophages (BMDMs) were isolated from myeloid-specific LDHA knockout mice derived from crossbreeding LysM-Cre transgenic mice and LDHA floxed mice. RNA sequencing and LC-MS/MS metabolomics analyses were used in this study to determine the effect of LDHA deletion on BMDM following stimulation with IFN-γ. LDHA deletion in IFN-γ BMDMs resulted in a significant alteration of the macrophage activation and functional pathways, and change in glycolytic, cytokine, and chemokine gene expression. Metabolite concentrations associated with pro-inflammatory macrophage profiles were diminished while anti-inflammatory-associated ones were increased in LDHA KO BMDMs. Glutamate and amino sugars metabolic pathways were significantly affected by the LDHA deletion. A combined muti-omics analysis highlighted changes in Rap1 signaling, cytokine-cytokine receptor interaction, focal adhesion, and MAPK signaling metabolism pathways. Deletion of LDHA in macrophages results in a notable reduction in the pro-inflammatory profile and concurrent upregulation of anti-inflammatory pathways. These findings suggest that LDHA could serve as a promising therapeutic target for inflammation, a key contributor to the pathogenesis of acute kidney injury.

Characterization of cerebrospinal fluid markers as indicators of spinal cord ischemia following an endovascular aortic aneurysm repair procedure.

Spinal cord ischemia (SCI) remains one of the most devastating complications in both open and endovascular stent graft repair of thoracoabdominal aortic aneurysms. The endovascular aortic aneurysm repair (EVAR) can be either thoracic (TEVAR) when it targets the thoracic aortic aneurysm or fenestrated branched when repair involves the visceral and/or renal arteries. Even though EVAR interventions are less invasive than open repair, they are still associated with a significant risk of SCI. The current primary strategy to prevent SCI after TEVAR is to increase and/or maintain spinal cord perfusion pressure (blood flow) by increasing the mean arterial pressure while simultaneously draining CSF. Although the benefit of CSF drainage in EVAR procedures remains uncertain, it provides an opportunity to study the changes in cytokine and oxidative stress markers that may signal the pathophysiology of SCI following EVAR. The aim of this study was to evaluate the temporal relationship between stent deployment and CSF cytokine and oxidative stress marker levels as predictors of delayed SCI in patients undergoing an EVAR procedure. There were 16 EVAR cases across 15 patients enrolled in this study, with 1 patient undergoing the procedure twice 1 year apart. The levels of oxidative stress (8-hydroxy-2'-deoxyguanosine [8-OHdG], glial fibrillary acidic [GFAP], and lactic acid) and proinflammatory (tumor necrosis factor-alpha [TNF-α], interleukin (IL)-6, and IL-1β) and antiinflammatory (IL-4) markers were quantified at different time points between 0 and 48 hours after EVAR by enzyme-linked immunosorbent assay. The changes in protein levels of both oxidative stress and inflammatory markers were expressed as fold change from the time of the lumbar drain insertion prior to surgery. Following the EVAR procedure, 8-OHdG resulted in the highest upregulation at later time points postoperatively (48 hours) and this increase was positively correlated with TNF-α level. The data also revealed that IL-6 peaked during the stent deployment intervention and this pattern of expression was positively correlated with the expression of lactic acid. No significant changes were noted in the expression levels of GFAP, lactic acid, and IL-1β. There appears to be a temporal relationship between lumbar CSF drainage and CSF cytokines and oxidative stress markers that may help 1) identify patients at risk for developing delayed SCI and 2) modify patient management to prevent the damage from delayed SCI.

Effect of fish consumption on the interactions between the gut microbiota and inflammatory markers: Results from the iFISH study

Dietary intake can influence immune function indirectly by affecting the gut microbiota composition and metabolism(1). Fish consumption has been shown to positively regulate the gut microbiota in humans(2,3);albeit in those studies fish was consumed in high amounts (500-750g/week) and immune function was not investigated. This study investigated the effect of consuming the UK dietary recommendation for fish(4) (2 portions [140-280g/week], one of which is oily) on the gut microbiota alpha diversity. Further, we examined if changes (pre- to post-intervention) in the gut microbiota composition were associated with changes in immune cytokine concentrations.An 8-week randomised controlled trial in low fish consuming women of childbearing age (n = 41; median age 23y) investigated the effect of consuming 1 or 2 portions of fish (tuna or sardines)/week compared to not consuming fish. A blood sample was collected to measure inflammatory cytokines (tumour necrosis factor-a, interleukin [IL]-1b, IL-5, IL-6, IL-17A and IL-22) pre-and post-intervention. Faecal samples were collected at both timepoints and extracted DNA was used to determine gut microbiota compositional profiles using 16S metagenomic sequencing (Illumina, USA). Statistical analysis investigated significant differences in changes in gut microbiota alpha diversity and compositional relative abundances between fish intervention (N = 26) and control (N = 15), then secondary analysis stratified by portion size (1 vs 2 portions) and type of fish (tuna vs sardines). Differences in cytokines between fish intervention and control were assessed by Mann-Whitney U. Spearman rank coefficient assessed associations between the changes in gut microbiota relative abundances with cytokine changes in fish and control groups.Fish consumption increased gut microbiota alpha diversity indices (Chao1 [7.37 ± 41.23], Simpson [0.003 ± 0.163], Shannon [0.07 ± 0.33], phylogenetic diversity [0.35 ± 2.59], observed species [9.00 ± 40.06]), albeit this was not significant compared to the control group (p&gt;0.05). Consumption of fish, specifically sardines, for 8 weeks significantly reduced Bacteroidetes (-4.77 ± 4.88%) when compared to control (+4.15 ± 7.58%) (p&lt;0.01). No significant differences were observed between the change in relative abundances of gut microbiota at genus-level taxa or inflammatory cytokines between the fish intervention and control. In the fish intervention group, increases in IL-17A, IL-22 and IL-6 concentrations were positively correlated with changes in Alistipes, Rhodococcus, Haemophilus, Barnesiella and Akkermansia relative abundances (p&lt;0.05).Although not statistically significant, consistent findings suggest that fish intake, in line with dietary guidelines, may have favourable impact on gut microbiota. Sardines, oily fish rich in n-3 polyunsaturated fatty acids, may have health benefits in disease states where Bacteroidetes is elevated; nevertheless, further research is required in a larger cohort over a longer period.

MicroRNA-146a-5p protects retinal ganglion cells through reducing neuroinflammation in experimental glaucoma.

Neuroinflammation plays important roles in retinal ganglion cell (RGC) degeneration in glaucoma. MicroRNA-146 (miR-146) has been shown to regulate inflammatory response in neurodegenerative diseases. In this study, whether and how miR-146 could affect RGC injury in chronic ocular hypertension (COH) experimental glaucoma were investigated. We showed that in the members of miR-146 family only miR-146a-5p expression was upregulated in COH retinas. The upregulation of miR-146a-5p was observed in the activated microglia and Müller cells both in primary cultured conditions and in COH retinas, but mainly occurred in microglia. Overexpression of miR-146a-5p in COH retinas reduced the levels pro-inflammatory cytokines and upregulated the levels of anti-inflammatory cytokines, which were further confirmed in the activated primary cultured microglia. Transfection of miR-146a-5p mimic increased the percentage of anti-inflammatory phenotype in the activated BV2 microglia, while transfection of miR-146a-5p inhibitor resulted in the opposite effects. Transfection of miR-146a-5p mimic/agomir inhibited the levels of interleukin-1 receptor associated kinase (IRAK1) and TNF receptor associated factor 6 (TRAF6) and phosphorylated NF-κB subunit p65. Dual luciferase reporter gene assay confirmed that miR-146a-5p could directly target IRAK1 and TRAF6. Moreover, downregulation of IRAK1 and TRAF6 by siRNA techniques or blocking NF-κB by SN50 in cultured microglia reversed the miR-146a-5p inhibitor-induced changes of inflammatory cytokines. In COH retinas, overexpression of miR-146a-5p reduced RGC apoptosis, increased RGC survival, and partially rescued the amplitudes of photopic negative response. Our results demonstrate that overexpression of miR-146a-5p attenuates RGC injury in glaucoma by reducing neuroinflammation through downregulating IRAK1/TRAF6/NF-κB signaling pathway in microglia.

Elevated Plasma IL-6 Coincides with Activation of STAT3 in PBMC After Acute Resistance Exercise.

Changes in plasma concentrations of anti-inflammatory cytokines, such as interleukin-6 (IL-6) and IL-10, after acute resistance exercise (RE) have been widely explored. Whether observed changes in plasma cytokine concentration correspond to the activation of anti-inflammatory signaling pathways in immune cells after acute RE is unknown. This study aimed to determine if changes in plasma cytokines after acute RE resulted in the activation of anti-inflammatory signaling pathways in peripheral blood mononuclear cells (PBMC). Healthy young males (N = 16; age = 23.5 ± 2.7 yr; BMI = 22.4 ± 1.7 kg·m-2) participated in a single session of whole-body RE (4 sets of 4 different exercises at 70% 1-repetition maximum with the last set to failure) and a sedentary control (CON) condition in a randomized crossover design. Blood samples were collected at several time points before and after the exercise bout. Higher plasma IL-6, IL-10, and IL-1 RA concentrations were observed after RE compared with CON. Phosphorylation of STAT3 and protein expression of SOCS3 in PBMC were increased in RE compared with CON. The elevation of plasma IL-6, but not IL-10, coincided with the activation of STAT3 signaling in PBMC. These results highlight a potential mechanism by which RE may exert anti-inflammatory actions in circulating immune cells.

Intrauterine inoculation of pseudorabies virus impairs mouse embryo implantation via inducing inflammation and apoptosis in endometrium.

Pseudorabies virus (PRV) is the pathogenic agent of pseudorabies, causing serious reproductive failure in swine. However, it is still unknown whether PRV uterine inoculation impairs blastocyst implantation. In the present study, a PRV infection mouse model was developed. Pregnant mice were inoculated with either 104 or 105 50% tissue culture infectious dose (TCID50) units of PRV on gestation day 2 (GD2). Viral DNA was detected in tissues by PCR and/or in situ hybridization. Histopathological change and expression of proinflammatory cytokines in uterus were analyzed by H.E. staining and qPCR, respectively. Apoptosis was also investigated by TUNEL assay, and the expression of apoptosis-related proteins including Bax and Bcl-2 was detected by Western blot. The results showed that intrauterine exposure of PRV on GD2 reduced the number of embryo implantation site. Abundant viral DNA was detected in spinal marrow and brain, and small amounts of PRV genomes were detected in embryo implantation site, ovary as well as thymus. Considerable inflammatory cells infiltrating in the endometrium, with high levels of pro-inflammatory cytokines of interleukin (IL)-6, IL-1β and tumor necrosis factor-α mRNA after infection. In addition, PRV infection promoted apoptosis in stroma and endothelium of the mouse endometrium. Collectively, intrauterine inoculation of PRV during early pregnancy causes cytokine release syndrome and apoptosis in endometrium, which impairs mouse embryo implantation.

Evaluation of the Activity of Olibanum Oil as an Immune Booster in Rats

The applications of herbal medicine have recently acquired growing interest in range of the prophylaxis and treatment of diseases. Olibanum has been used since ancient eras and several reports studied the pharmacological characteristics of boswellic acid, particularly their effect on the inflammatory response, analgesic properties, and anti-arthritic activity mostly in cell lines, but new approaches include animal models to assess these natural derivatives effects taking into consideration of being safer than synthetic preparations. The impact of olibanum oil on several parameters was studied in rats during this study. These included white blood cell (WBC) count, lactate dehydrogenase (LDH), and C reactive protein (CRP), as well as other pro-inflammatory cytokines like tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6), and the cytokine interleukin -10 (IL-10) that is anti-inflammatory. Total WBCs in addition to IL-10 levels significantly increased in the oil-treated group in comparison with the control one, while the rats treated with olibanum oil revealed a significant reduced level of LDH, CRP, IL-6 and TNF- α compared with the controls (p &lt; 0.05). These outcomes indicate that olibanum oil treatment are manifested by cytokine changes, it can improve the anti-inflammatory response and down-regulate the pro-inflammatory cytokines. So, the promising impact of olibanum oils as an immunomodulator could be used in alternative therapies.

Gross saponins of Tribulus terrestris attenuate rheumatoid arthritis by promoting apoptosis of fibroblast-like synoviocytes and reducing inflammation by inhibiting MAPK signalling pathway.

Among the numerous treatment options for rheumatoid arthritis (RA), the promotion of synoviocyte apoptosis and inhibition of inflammation are considered the most effective. However, the potential pro-apoptotic effects of gross saponins of Tribulus terrestris (GSTT), which are natural saponins derived from the herb Tribulus terrestris L., on rheumatoid arthritis fibroblast-like synoviocytes (RA-FLSs) and their essential molecular mechanisms remain unclear. The aim of the present study was to investigate the influence of different concentrations of GSTT on RA-FLSs using various assays, including cell counting kit-8 (CCK-8), reverse transcription polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), flow cytometry, terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) and western blot analysis. These assessments were conducted to evaluate the cell viability, changes in the levels of inflammatory cytokines, apoptosis rates and alterations in protein expression related to this process. In vivo, arthritis clinical score, haematoxylin and eosin (HE) staining and ELISA were used to assess paw inflammation, histopathology and serum inflammatory cytokine changes. Our findings demonstrated that GSTT substantially promotes the apoptosis of RA-FLSs and reduces pro-inflammatory cytokine levels. GSTT also reduced the Bcl-2/Bax ratio and inhibited JNK and p38 phosphorylation. Furthermore, GSTT exhibits positive effects on RA by improving clinical scores, reducing synovial inflammatory infiltration and lowering serum pro-inflammatory cytokine levels. Therefore, by promoting the apoptosis of RA-FLSs and suppressing inflammation through the inhibition of the MAPK signalling pathway, GSTT is a promising therapeutic intervention for RA.

Xianglian pill alleviates ulcerative colitis by inhibiting M1 macrophage polarization via modulation of energy metabolite itaconate

BackgroundXianglian pill (XLP) is a traditional Chinese medicine (TCM) that is widely used to treat ulcerative colitis (UC). However, its mechanism of action in UC is unclear. PurposeThis study aimed to investigate the mechanism of action of XLP in treating UC and role of M1 macrophage polarization in this process. Study designIn vivo experiments were performed using UC mice while in vitro experiments were conducted using RAW264.7 cells. MethodsMice were administered 3 % dextran sulfate to induce UC model and then treated with XLP. Changes in histopathology and pro-inflammatory cytokines were evaluated. The levels of M1 macrophages in mesenteric lymph nodes were detected by flow cytometry. Colon metabolite levels were analyzed using an energy metabolomic assay. To assess itaconate's impact, both in vivo (mice) and in vitro (RAW264.7 cells) models were employed. Immunofluorescence staining was used to measure the expression levels of TNF-α, IL-6, and iNOS, while qRT-PCR was utilized to quantify the mRNA levels of TET2, STAT1, and Nfkbiz. ResultsXLP alleviated ulcerative damage and reduced TNF-α and IL-6 levels in colon, and also downregulated the levels of M1 macrophages and modulated the state of energy metabolism. Specifically, XLP significantly increased ITA level in colonic tissue and this increase was significantly associated with decreased levels of M1 macrophages and alleviation of UC following XLP treatment. Moreover, ITA directly suppressed the polarization of macrophage from M0 to M1 phenotype, accompanied by the decrease of TNF-α, IL-6, and iNOS levels. Further, ITA decreased inflammatory responses in M1 macrophage by inhibiting the TET2/STAT1 and TET2/NF-κB signaling pathways. ConclusionXLP can treat UC by suppressing M1 macrophage polarization via increasing the level of energy metabolite ITA.

Effect of different delayed cooling time on organ injuries in rat models of exertional heat stroke

To investigate how the timing of cooling therapy affects organ injuries in rats with exertional heat stroke (EHS) and explore the possible mechanisms. A total of 60 adult male Wistar rat models of EHS were randomized into model group without active cooling after modeling, immediate cooling group with cold water bath immediately after modeling, delayed cooling groups with cold water bath at 5, 15 and 30 min after modeling, with another 12 mice without EHS as the normal control group. The changes in core body temperature of the mice were recorded and the cooling rate was calculated. After observation for 24 h, the mice were euthanized and blood samples were collected for detection of interleukin-1β (IL-1β), IL-2, IL-4, IL-6, IL-10, and interferon-γ, followed by pathological examination of the vital organs. The rats that died within 24 h were immediately dissected for examination. The number of deaths of the model rats within 24 h increased significantly with the time of delay of cooling treatment. The delay of cooling was positively correlated (r=0.996, P=0.004) while the cooling rate negatively correlated with the mortality rate (r=-0.961, P=0.009). The inflammatory cytokine levels presented with different patterns of variations among the cooling intervention groups. All the rat models of EHS had significant organ damages characterized mainly by epithelial shedding, edema, effusion, and inflammatory cell infiltration, and brain and renal injuries reached the peak level at 24 h after EHS. EHS causes significant nonspecific pathologies of varying severities in the vital organs of rats, and the injuries worsen progressively with the delay of cooling. There is a significant heterogeneity in changes of serum inflammatory cytokines in rats with different timing of cooling intervention following EHS.

Dynamic changes of cytokines in COVID-19 and in the post-COVID period

Dynamic changes of cytokines in COVID-19 and in the post-COVID period

Monocyte subsets in breast cancer patients under treatment with aromatase inhibitor and mucin-1 cancer vaccine

BackgroundMonocytes comprise subsets of classical, intermediate and non-classical monocytes with distinct anti- or pro-tumor effects in breast cancer (BC). They are modulated by estrogen, and can contribute to BC control by endocrine therapy in preclinical models.MethodsTo elucidate whether changes in monocyte subsets are associated with treatment and response, we investigated peripheral blood samples of 73 postmenopausal women with estrogen receptor (ER) positive BC, who received aromatase inhibitor therapy with or without the mucin-1 vaccine tecemotide in the ABCSG34 trial. Blood was retrieved at baseline, midterm and end of therapy, and was analyzed for the distribution and ER expression of monocyte subsets by flow cytometry.ResultsWhen 40 healthy, age-matched women were compared with BC patients before treatment start, ER levels of monocytes did not differ, yet patients presented with a higher frequency of classical and fewer non-classical monocytes. Endocrine therapy triggered a significant increase in ER levels in all monocyte subsets, without affecting subset distribution. Vaccination had no overall impact on subset frequency and ER expression. Yet, a shift from intermediate to classical monocytes during therapy correlated with changes in plasma cytokines and chemokines and was significantly associated with low residual cancer burden in vaccinated patients. Without tecemotide, baseline ER levels in classical monocytes were significantly higher in women with good response to endocrine therapy.ConclusionsThis study identified classical monocytes to be associated with ER positive BC and with patient response to neoadjuvant endocrine treatment and cancer vaccination.

Lacticaseibacillus rhamnosus LRa05 mediates dynamic regulation of intestinal microbiota in mice with low-dose DSS-induced chronic mild inflammation.

This study aimed to investigate the effects of low-dose dextran sulfate sodium (DSS) on the induction of chronic mild inflammation in mice and to evaluate the therapeutic potential of Lacticaseibacillus rhamnosus LRa05 (LRa05) to ameliorate the associated effects. The focus was on investigating changes in inflammatory, gut microbiota, serum lipopolysaccharide (LPS) and inflammatory cytokines. Mice were exposed to a low-dose of DSS to induce chronic mild inflammation and LRa05 was administered as a probiotic intervention. The experiment included determination of body weight, colon length, histological examinations, and analysis of LPS and inflammatory cytokines in serum over 12 weeks. In addition, liver function, oxidative stress and intestinal microbiota were examined to understand the comprehensive effects of DSS and LRa05. Low-dose DSS did not lead to significant changes in body weight, colon length or histologic signs of inflammation. However, it led to a significant increase in serum levels of LPS, tumor necrosis factor-alpha (TNFα) and interleukin-6 (IL6). Intervention with LRa05 effectively attenuated these changes, particularly by lowering LPS levels and normalizing inflammatory cytokines. In addition, LRa05 protected against DSS-induced liver function damage and attenuated oxidative stress in the liver. Analysis of the gut microbiota demonstrated dynamic regulatory effects, where LRa05 intervention led to significant shifts in microbial populations, promoting a balanced microbiota profile. These changes are indicative of dynamic regulation by LRa05 in response to chronic mild inflammation, highlighting the probiotic's role in modulating the gut environment. The LRa05 intervention showed multi-layered regulation in the chronic mild inflammation model by reducing inflammatory cytokines, maintaining liver function and restoring the balance of the gut microbiota. This provides experimental support for the potential use of LRa05 in chronic inflammation-related diseases and emphasizes the importance of probiotics for overall health. The study suggests that LRa05 is a potential therapeutic agent for the treatment of chronic inflammation associated with gut dysbiosis.

Alterations and clinical value of peripheral lymphocyte subsets and inflammatory factors in paragangliomas.

Given the pivotal role of immune and inflammatory responses in tumor patients, the present study aimed to explore alterations and the clinical value of peripheral lymphocyte subsets and inflammatory factors in pheochromocytomas/paragangliomas (PPGLs). The clinical data of 327 patients, including 102 patients with metastatic PPGLs, were retrospectively analysed. Peripheral lymphocyte subsets were determined by flow cytometry. Relationships between immune and inflammatory parameters and clinicopathological characteristics were evaluated by intergroup comparisons and correlation analyses. Univariate and multivariate logistic regression analyses were employed to identify metastatic indicators. The corresponding nomogram was constructed and evaluated for discrimination and calibration. The median age at diagnosis was 45.0 years, and duration of follow-up was 3.0 years. Compared with those in younger patients (<45.0 years), most lymphocyte subsets were significantly reduced in older patients (≥45 years) (P<0.05). The count of lymphocytes, CD3+T cells and CD4+T cells were negatively correlated with 24h-urinary epinephrine and plasma metanephrine levels (R=-0.2∼-0.1, P<0.05). In addition, patients with lymph node (n=37) or bone metastases (n=41) had a lower percentage of CD4+T cells (P<0.05). Multivariate analysis revealed that CD3+T cell≥1446.50/μl, CD4+T cell%<39.95%, CD8+T cell%<24.95%, CD4+/CD8+T cell ratio<2.88, B cell%≥8.65%, TNF-alpha<12.45pg/ml, IL8<30.50pg/ml and PLT≥269.50*109/L were significant indicators of metastatic PPGLs. The area under the curve (AUC) of the nomogram was 0.800 (95% CI: 0.736-0.865). Immunesenescence, characterized by immune dysfunction with aging, was observed in PPGLs. Higher epinephrine and metanephrine levels might impair host's immune response. Monitoring changes in peripheral lymphocyte subsets and serum cytokines could indicate patients' conditions, especially the occurrence of metastasis.